Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives

Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the
enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks,
characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion,
hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations
and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney
disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent
attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis
of AHP can be made with a test for urinary porphobilinogen, -aminolaevulinic acid and porphyrins using a
single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical
symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as
some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe,
potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations
in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management
of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated
as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based
agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for
the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate
porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges,
and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations.